A5039670277- Gene Regulatory Network Analysis
- Single-cell and spatial transcriptomics
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- RNA and protein synthesis mechanisms
- Animal Genetics and Reproduction
- Pluripotent Stem Cells Research
- RNA modifications and cancer
- CAR-T cell therapy research
- Cancer-related gene regulation
- Gene expression and cancer classification
- Asthma and respiratory diseases
- IL-33, ST2, and ILC Pathways
- Psoriasis: Treatment and Pathogenesis
- Viral Infectious Diseases and Gene Expression in Insects
- Plant Virus Research Studies
- Viral-associated cancers and disorders
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- T-cell and Retrovirus Studies
- Neural Networks and Reservoir Computing
- Tissue Engineering and Regenerative Medicine
University of Chicago
2011-2024
Johns Hopkins University
2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2020
Howard Hughes Medical Institute
2011-2013
Innate-like NKT cells conspicuously accumulate within the liver microvasculature of healthy mice, crawling on luminal side endothelial cells, but their general recirculation pattern and mechanism intravascular behavior have not been elucidated. Using parabiotic we demonstrated that, despite location, most failed to recirculate. Antibody blocking experiments established that they were retained locally through constitutive LFA-1–intercellular adhesion molecule (ICAM) 1 interactions. This...
Abstract RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report discovery a novel allosteric binding site on nuclear receptor RORγt. Co-crystallization ligand domain (LBD) series small-molecule antagonists demonstrates occupancy previously unreported pocket. Binding at this non-canonical induces an unprecedented conformational reorientation helix 12 in LBD, which blocks cofactor binding. The functional...
Cellular heterogeneity in gene expression is driven by cellular processes, such as cell cycle and cell-type identity, environment spatial location. The cycle, particular, thought to be a key driver of cell-to-cell expression, even otherwise homogeneous populations. Recent advances single-cell RNA-sequencing (scRNA-seq) facilitate detailed characterization can thus shed new light on the processes driving heterogeneity. Here, we combined fluorescence imaging with scRNA-seq measure phase levels...
Dynamic and temporally specific gene regulatory changes may underlie unexplained genetic associations with complex disease. During a dynamic process such as cellular differentiation, the overall cell type composition of tissue (or an in vitro culture) profile each can both experience significant over time. To identify these effects high resolution, we collected single-cell RNA-sequencing data differentiation time course from induced pluripotent stem cells to cardiomyocytes, sampled at 7...
Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation Th17 differentiation and function. was initially identified as a transcription factor required for thymopoiesis by maintaining survival CD4+CD8+ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how inhibition may impact thymocyte development. In this study, we show that in addition regulating DP thymocytes survival, also controls genes...
While comparative functional genomic studies have shown that inter-species differences in gene expression can be explained by corresponding genetic and epigenetic regulatory mechanisms, co-transcriptional such as alternative polyadenylation (APA), received little attention. We characterized APA lymphoblastoid cell lines from six humans chimpanzees identifying estimating the usage for 44,432 sites (PAS) 9518 genes. Although is largely conserved, 1705 genes showed significantly different PAS...
Abstract Background Comparative gene expression studies in apes are fundamentally limited by the challenges associated with sampling across different tissues. Here, we used single-cell RNA sequencing of embryoid bodies to collect transcriptomic data from over 70 cell types three humans and chimpanzees. Results We find hundreds genes whose regulation is conserved types, as well likely evolves under directional selection one or a handful types. Using human-chimpanzee fused line, also infer...
Practically all studies of gene expression in humans to date have been performed a relatively small number adult tissues. Gene regulation is highly dynamic and context-dependent. In order better understand the connection between complex phenotypes, including disease, we need be able study more cell types, tissues, states that are relevant human phenotypes. particular, characterize early development as mutations affect developmental processes may particular relevance traits. To address this...
Abstract Motivation The universal expressibility assumption of Deep Neural Networks (DNNs) is the key motivation behind recent worksin systems biology community to employDNNs solve important problems in functional genomics and moleculargenetics. Typically, such investigations have taken a ‘black box’ approach which internal structure themodel used set purely by machine learning considerations with little consideration representing internalstructure biological system mathematical DNN. DNNs...
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment autoimmune diseases. nuclear hormone receptor RORγt is a master regulator cells affects production host cytokines, including IL-17A, IL-17F, IL-22, IL-26, GM-CSF. Substantial interest been spurred across both academia industry to seek small molecules suitable inhibition. A variety inhibitors have reported in past few years, majority which are orthosteric...
Models that incorporate specific chemical mechanisms have been successful in describing the activity of Drosophila developmental enhancers as a function underlying transcription factor binding motifs. Despite this, minimum set required to reconstruct an enhancer from its constituent parts is not known. Synthetic biology offers potential test sufficiency known describe enhancers, well uncover constraints on number, order, and spacing Using functional model silico compensatory evolution, we...
Abstract Identifying the molecular effects of human genetic variation across cellular contexts is crucial for understanding mechanisms underlying disease-associated loci, yet many cell-types and developmental stages remain underexplored. Here we harnessed potential heterogeneous differentiating cultures ( HDCs ), an in vitro system which pluripotent cells asynchronously differentiate into a broad spectrum cell-types. We generated 53 donors collected single-cell RNA-sequencing data from over...
Metazoan gene expression is controlled through the action of long stretches noncoding DNA that contain enhancers—shorter sequences responsible for controlling a single aspect gene’s pattern. Models built on thermodynamics have shown how enhancers interpret protein concentration in order to determine specific levels expression, but emergent regulatory logic complete locus shows qualitative and quantitative differences from isolated enhancers. Such may arise steric competition limiting...
Organisms must ensure that expression of genes is directed to the appropriate tissues at correct times, while simultaneously ensuring these gene regulatory systems are robust perturbation. This idea captured by a mathematical concept called r-robustness, which says system perturbation in up r − 1 randomly chosen parameters. r-robustness implies biological has small number sensitive parameters and this can be used as robustness measure. In work we use investigate regulation using sequence...
Abstract Cellular heterogeneity in gene expression is driven by cellular processes such as cell cycle and cell-type identity, environment spatial location. The cycle, particular, thought to be a key driver of cell-to-cell expression, even otherwise homogeneous populations. Recent advances single-cell RNA-sequencing (scRNA-seq) facilitate detailed characterization heterogeneity, can thus shed new light on the driving heterogeneity. Here, we combined fluorescence imaging with scRNA-seq measure...
Abstract The universal expressibility assumption of Deep Neural Networks (DNNs) is the key motivation behind recent work in system biology community to employ DNNs solve important problems functional genomics and molecular genetics. Because black box nature DNNs, such assumptions, while useful practice, are unsatisfactory for scientific analysis. In this paper, we give an example a DNN which every layer interpretable. Moreover, biologically validated predictive. We derive our from systems...
Abstract Comparative gene expression studies in apes are fundamentally limited by the challenges associated with sampling across different tissues. Here, we used single-cell RNA-sequencing of embryoid bodies ( EBs ) to collect transcriptomic data from over 70 cell types three humans and chimpanzees. We found hundreds genes whose regulation is conserved types, as well likely evolves under directional selection one or a handful types. Using human-chimpanzee fused line, also inferred proportion...
Abstract Dynamic and temporally specific gene regulatory changes may underlie unexplained genetic associations with complex disease. During a dynamic process such as cellular differentiation, the overall cell type composition of tissue (or an in vitro culture) profile each can both experience significant over time. To identify these effects high resolution, we collected single-cell RNA-sequencing data differentiation time course from induced pluripotent stem cells to cardiomyocytes, sampled...